Jane-Jen Wang

In vitro Antitumor and Antimicrobial Activities of N-Substituents of Maleimide by Adamantane and Diamantane

New N-1-adamantylcitraconimide (compound 1) and N-1-diamantylcitraconimide (compound 2) were synthesized by reaction of citraconic anhydride with 1-aminoadamantane, and 1-aminodiamantane, respectively, followed by imidization with acetic anhydride and sodium acetate. Compound 1, N-1-adamantylmaleimide (compound 3) and N-1-diamantylmaleimide (compound 4) exhibited strong growth-inhibitory activity against four cancer cell lines (Colo 205, Hep G2, SK-BR-3 and Molt-4). Moreover, compound 1 showed relatively specific cytotoxicity against the test tumor cell lines. Compound 2 exhibited growth inhibitory activity against Colo 205, and SK-BR-3 cells, similar to 5-fluorouracil. It was noted that compound 2 showed relatively low cytotoxicity against Molt-4 cells, approximately 42 times lower than 5-fluorouracil. The N-substituents of imides with adamantly substituents have a more potent antitumor activity than the imides with diamantyl substituents. The imides with methyl substituents (compounds 1 and 2) showed relatively higher selectivity against the tested cancer cell lines than the imides without methyl substituents (compounds 3 and 4). Compounds 3 and 4 show good in vitro activities against Staphylococcus aureus and Trichophyton mentagrophytes. Compound 1 had weak antimicrobial activity against T. mentagrophytes.

Synthesis and characterization of new poly(N-1-adamantylmaleimide) and poly(N-1-diamantylmaleimide)

N-l-Diamantylmaleimide was synthesized by reaction of maleic anhydride with 1-aminodiamantane, followed by dehydration with acetic anhydride and sodium acetate. Poly(N-1-adamantylmaleimide) (IIa) and poly(N-l-diamantylmaleimide) (IIb) were polymerized using 2,2′-azobisisobutyronitrile (AIBN) as an initiator under different experimental conditions such as various initiator concentrations, solvents, polymerization temperatures, and polymerization times. Polymerizations of N-l-adamantylmaleimide in benzene at 60°C or in bulk gave polymers with molecular weights (2000–9500). The experimental results indicated that the propagation may be interrupted by steric hindrance of bulky and rigid substituents such as the adamantyl or diamantyl groups. In addition, the effect of chain transfer to monomer contributes to the relatively low activation energy. The glass transition temperatures of Ia and Ib were 204 and 216°C, respectively. The temperatures at 5% weight loss of the polymers IIa and IIb were above 412°C.

Induction of growth inhibition and G1 arrest in human cancer cell lines by relatively low-toxic diamantane derivatives.

We describe the discovery of a novel series of antitumor diamantane derivatives which induces G1 arrest in Colo 205 cells. Eight diamantane derivatives were screened for their activity in vitro against 60 human cancer cell lines in the National Cancer Institute (NCI)s anticancer drug screen. The relationships between structure and in vitro antitumor activity are discussed. The structure–activity relationship (SAR) study of diamantane derivatives clarified that the conformation of 1,6-bis(4-(4-aminophenoxy)-phenyl)diamantane (1,6-DPDONH2) was essential for significant antitumor activity. Very strong growth inhibition of 1,6-DPDONH2 (NSC-706829) was observed against one colon cancer line (Colo 205), four melanoma lines (MALME-3M, M14, SK-MEL-5 and UACC-257) and two breast cancer lines (MDA-MB-435 and MDA-N) with GI50 <1.0 μM, i.e. below 0.01, 0.23, 0.48, 0.5, 0.32, 0.26 and 0.28 μM, respectively. 1,6-DPDONH2 also exhibited particular selectivity against one colon cancer line (Colo 205), four melanoma lines (MALME-3M, M14, SK-MEL-5 and UACC-257) and two breast cancer lines (MAD-MB-435 and MDA-N) with GI50≤0.5 μM. In the same cancer subpanel, the selectivity of 1,6-DPDONH2 between these seven most sensitive lines and the least sensitive line ranged from 40- to 100-fold. With the exception of melanoma lines, 1,6-bis(4-(4-amino-3-hydroxyphenoxy)-phenyl)diamantane (1,6-DPD/OH/NH2) (NSC-706831) possessed stronger activity than 1,6-DPDONH2 against almost all tested cancer lines. Very strong growth inhibition of 1,6-DPD/OH/NH2 was observed against one leukemia line (HL-60(TB)), one NSCLC line (HOP-92), one ovarian cancer line (OVCAR-8) and one breast cancer line (T-47D) with GI50 <1.0 μM, i.e. 0.50, 0.85, 0.62 and 0.75 μM, respectively.

Dimethyladamantylmaleimide-induced in vitro and in vivo growth inhibition of human colon cancer Colo205 cells.

The effect of N-1-(3,5-dimethyladamantyl)maleimide (DMAMI) on the growth of Colo205 human colon cancer cells was examined both in vitro and in vivo. Flow cytometry analysis showed a decrease of G2/M Colo205 cells at 4–6 h after treatment with DMAMI prior to accumulation of apoptotic cells at 24 h. Significant changes in cell morphology, i.e. shrinkage and chromatin condensation of cells, were observed after treatment with DMAMI. In the analysis of the apoptosis markers, it was found that the increase of Annexin V binding to membrane, peroxide radicals, dissipation of the mitochondrial membrane potential, and the activation of caspase-3, -8 and -9 were all evident at 4–6 h after treatment with DMAMI. In vivo analysis showed that treatment of Colo205 tumor-bearing SCID mice with DMAMI (230 mg/kg, intratumoral, once) resulted in rapid tumor damage that leads to significant tumor growth inhibition and no obvious acute toxicity. These results suggest that DMAMI has potential for local treatment of cancer.

Synthesis of 1,6-diaminodiamantane

Abstract A new polycyclic diamine, 1,6-diaminodiamantane, was synthesized starting from 1,6-dibromodiamantane. The reaction of 1,6-dibromodiamantane with acetonitrile using H 2 SO 4 as catalyst afforded 1,6-diacetamidodiamantane in 72% yield. The reaction of 1,6-diacetamidodiamantane with NaOH afforded 1,6-diaminodiamantane in 50% yield.

Biological activities of new poly(N 1-adamantylmaleimide) and poly(N-1-diamantylmaleimide)

N-1-Diamantylmaleimide was synthesized by reaction of maleic anhydride with 1-aminodiamantane, followed by dehydration with acetic anhydride and sodium acetate. Poly(N-1-adamantylmaleimide) (IIa) and poly(N-1-diamantylmaleimide) (IIb) were synthesized by free radical polymerization. N-1-Adamanlylmaleimide (Ia) and N-1-diamantylmaleimide (Ib), exhibited strong activities in vitro antitumor activities. Interestingly, poly(N-1-adamantylmaleimide) exhibited growth inhibitory values against Colo 205, Hep G2, and SK-BR-3, similar to 5-Fluorouracil. It was noted that poly(N-1-adamantylmaleimide) showed relatively lower cytotoxicity against Molt-4 cells than against Colo 205, Hep G2, and SK-BR-3 cells. The decreasing antitumor activities against individual tumor cell line were in the order Ia > Ib > IIa > IIb. This result shows that N-substituents of maleimides play an important role in their antitumor activity. Additionally, Ia and Ib show good in vitro activity against staphylococcus aureus ATCC 25923 while polymers IIa and IIb exhibited weak activity against S. aureus ATCC 25923.